Azithromycin for the treatment of nodular acne

ABSTRACT

Azithromycin, administered systemically, is an effective treatment for nodules associated with acne vulgaris.

This application claims the benefit of pending U.S. patent applicationSer. No. 11/635,127, filed Dec. 6, 2006, which is to issue as U.S. Pat.No. 7,704,959 on Apr. 27, 2010, which application claimed the benefit ofU.S. Provisional Patent Application Ser. No. 60/849,065, which was filedon Oct. 3, 2006.

FIELD OF THE INVENTION

The invention pertains to the field of antibiotic therapy, particularlyazithromycin, to combat skin disease and particularly to the use ofazithromycin to treat acne vulgaris. In particular, the inventionpertains to the field of the treatment of acne nodules, such as due tonodular acne, and most particularly to the treatment of severe nodularacne vulgaris.

BACKGROUND OF THE INVENTION

Acne vulgaris, often referred to simply as acne, is a common skindisease that typically, although not exclusively, affects adolescents.When untreated, most cases of acne persist for several years and thenspontaneously remit, usually when an individual is in the mid-twenties.

The etiology of acne is multi-factorial. The disease is thought tooriginate primarily due to increased production of sebum,hypercornification of the infundibulum of pilosebaceous glands,proliferation of microbial flora especially Propionibacterium acnes, andsubsequent inflammation. The normal process of epidermal maturation,called keratinization, involves the growing and shedding of cells thatline the pores and glands of the skin. In acne, this process isdisrupted, causing an overproduction of epithelial cells(hyperkeratosis) in the follicular infundibulum of the sebaceous glandduct, forming a blockage of the pore.

The resulting lesions can be divided into inflammatory andnon-inflammatory lesions. Non-inflammatory lesions, classified as openand closed comedones, are commonly known as blackheads and whiteheads,respectively. Cases of acne presenting solely non-inflammatory lesionsare sometimes referred to as mild acne.

Inflammatory lesions are a result of excessive growth of the commonbacteria, Propionihacterium acnes, and its interaction with the normaloils of the skin (sebum), resulting in the generation of byproducts thatelicit an inflammatory reaction. In addition to these primary lesions,patients may also suffer from scars as a complication of inflammatorylesions.

Inflammatory lesions of acne may be divided into two groups. Less severecases of acne are associated with pustules and papules, as well as withnon-inflammatory lesions. Papules are inflamed, red, tender bumps withno head that range from 2 to 5 mm in diameter. Pustules are papules thatare superficial and contain grossly purulent material, that is they havea head with a white or yellow center. Depending on the number of papulesand pustules present, papulopustular acne cases may be graded in a rangefrom moderate to severe acne. Individuals with severe cases ofpapulopustular acne may also have one or two acne nodules or cysts.

More severe cases of acne are associated with nodules and cysts as apredominant lesion. Such individuals present with three or more nodulesand typically also have multiple other inflammatory lesions, such aspustules and papules, and non-inflammatory lesions, such as comedones.Cysts and nodules are blockages of the oil glands of the skin that haveburst open and produced inflammation and pus in the surrounding tissues.Nodules are large, hard bumps 5 mm or more in diameter present under orwithin the surface of the skin, which can be painful and can last formany months. Cysts are similar to nodules but are pus-filled. Cases ofacne presenting with inflammatory acne with cysts and/or nodules areoften referred to as severe acne.

However, since there is no accepted definition for the term “severeacne” and often papular or pustular acne is referred to as severe acne,it is preferred to refer to cases of acne presenting with cysts and/ornodules by the more specific term of “nodular” acne.

The Food and Drug Administration has recognized that nodular acne is adistinct entity that is to be considered independently of other, milderforms of acne. In the Draft Guidance for Industry—Acne Vulgaris:Developing Drugs for Treatment, issued in September 2005 by the U.S.Department of Health and Human Services, Food and Drug Administration,Center for Drug Evaluation and Research (CDER), the IGA Scale for AcneVulgaris was utilized to grade the severity of non-nodular acne for thepurposes of clinical trials of topical drugs. The IGA Scale for AcneVulgaris, as depicted in the Draft Guidance for Industry, is as shown inTable 1.

TABLE 1 Grade Description 0 Clear skin with no inflammatory ornoninflammatory lesions 1 Almost clear; rare noninflammatory lesionswith no more than one small inflammatory lesion 2 Mild severity; greaterthan Grade 1; some noninflammatory lesions with no more than a fewinflammatory lesions (papules/pustules only, no nodular lesions) 3Moderate severity; greater than Grade 2; up to many noninflammatorylesions and may have some inflammatory lesions, but no more than onesmall nodular lesion 4 Severe; greater than Grade 3; up to manynoninflammatory and inflammatory lesions, but no more than a few nodularlesions

In the Draft Guidance for Industry, immediately below the IGA Scale, theFDA further distinguishes nodulocystic acne from other forms of acne andstates that, “It is recommended that enrollment of acne vulgarispatients not include patients with nodulocystic acne.” The DraftGuidance for Industry also states that because there are specificinformation needs with regard to treatment for nodular acne, applicantsshould seek additional guidance from the FDA regarding treatments thatare targeted for nodular/nodulocystic acne.

Mild acne is typically treated with topical cleansers and benzoylperoxide. Moderate inflammatory acne is often treated with cleansers andkeratolytic or comedolytic agents such as retinoids (tretinoin,adapalene or tazaratene), salicylic acid or alphahydroxy acids, often incombination with topical or systemic antibiotics. Systemic antibiotics,including tetracycline, minocycline, doxycycline, erythromycin, andazithromycin, have been used successfully to treat pustular or papularacne. In May 2006, the Food and Drug Administration approved SOLODYN™(minocycline HCl, Medicis Pharmaceutical Corp., Scottsdale, Ariz.) fortreatment of non-nodular moderate to severe acne. The prescribinginformation on the package insert for Solodyn™ as approved by the FDAspecifically states that “Solodyn™ is indicated to treat onlyinflammatory lesions of non-nodular moderate to severe acne vulgaris.”To date, no antibiotic has been shown to be effective or has beenapproved by the FDA for treatment of nodular acne.

In cases of nodular acne, a dermatologist will often prescribeisotretinoin (ACCUTANE®, Roche Laboratories, Inc., Nutley, N.J.).Isotretinoin has been found to be effective in clearing nodular acnelesions. The drug works by reducing the size of oil glands in the skinso that much less oil is produced and the growth of bacteria isdecreased.

The use of isotretinoin, however, has severe disadvantages. Isotretinoinhas been shown to cause birth defects in the developing fetus and,therefore, pregnant women should not use isotretinoin. Additionally,isotretinoin has been associated with depression and suicidal thoughtsin users. Because of the dangers associated with the use ofisotretinoin, the FDA has initiated a program to permit only registeredpharmacies and health care providers to dispense isotretinoin and toclosely monitor the prescriptions and any adverse reactions occurring inpatients receiving isotretinoin.

Because of the severe side effects of isotretinoin, there is currentlyno safe, approved therapy for treating nodular acne vulgaris.

Pigatto et al, “Isotretinoin versus Minocycline in Cystic Acne: A Studyof Lipid Metabolism”, Dermatologica, 172:154-159 (1986) compared theefficacy of treatment of nodular cystic acne with isotretinoin and withminocycline, a member of the tetracycline family of antibiotics. Pigattofound that isotretinoin was highly efficacious in treating nodularcystic acne. In contrast, Pigatto found that, although minocycline wasinitially effective in reducing the number and size of nodules andcysts, treatment with minocycline beyond 4 weeks resulted in no furtherimprovement. Moreover, treatment with minocycline did not, at any timeduring the study, decrease the number or size of cysts to a level thatwould be considered to be less than severe. As shown in FIG. 1 ofPigatto, treatment with minocycline reduced the number of cysts from anaverage of 20 to 10 during the first 10 weeks of treatment, but thatfurther treatment with minocycline did not further decrease the numberof cysts in the patients. Likewise, initial 10 week treatment withminocycline reduced the average diameter of cysts from 15 mm to 8 mm,but further treatment failed to produce any further reduction indiameter. In fact, after 20 weeks of treatment, average cyst diameterhad increased once again to 10 mm. The Pigatto study establishes thatminocycline is not an effective therapy for treatment of nodular acne.

The question of whether minocycline could be an effective therapeuticagent for nodular acne when used in combination with an additionalanti-acne therapy was studied in Gollnick et al. “Comparison of CombinedAzaleic Acid Cream Plus Oral Minocycline with Oral Isotretinoin inSevere Acne”, Eur. J. Dermatol., 11:538-544 (2001). Gollnick evaluatedpatients treated for six months with a combination of oral minocyclineand topically applied azaleic acid cream and found that treatment aftertwo months with this combination resulted in a decrease of 60% in numberof deep acne lesions (cysts and nodules) and a decrease of 100% afterfour months. Thus, minocycline is an effective therapy for nodular acnewhen combined with topically applied azaleic acid.

The mode of action of minocycline and other tetracycline antibiotics intreating lesions of acne is uncertain. Ashley, U.S. Patent ApplicationPublication No. 2004/0147492 discloses that tetracycline compounds,including minocycline and doxycycline, are effective in treating acnewhen administered to an individual in an amount that has substantiallyno antibiotic effect. The data of Ashley indicates that it is somethingother than the antibiotic effect of these drugs that provides thefavorable anti-acne effect, although what the anti-acne mode of actionof the tetracyclines is has not been determined. Because it is not theantibiotic activity of these compounds that provides their anti-acneeffect, it is clear that one cannot extrapolate the level ofeffectiveness of tetracycline antibiotics in the treatment of acne toantibiotics that are not members of the tetracycline family.

Azithromycin is the generic name for9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, a broad spectrumantibiotic derived from erythromycin A. It was independently discoveredby Bright, U.S. Pat. No. 4,474,768 and Kobrehel, U.S. Pat. No.4,517,359, where it was referred to by the name ofN-methyl-11-aza-10-deoxo-10-dihydroerythromycin A. Bright and Kobreheldisclosed azithromycin as a hygroscopic form. Allen, U.S. Pat. No.6,268,489, discloses a non-hygroscopic dihydrate form of azithromycin.Both the monohydrate form and the dihydrate form are effective intreating bacterial infections when administered systemically.

Several scientific articles have published studies concerning theefficacy of azithromycin in treating lesions of inflammatory acne.Fernandez-Obregon, “Azithromycin for the Treatment of Acne,”International Journal of Dermatology, 39:45-50 (2000), discloses thatazithromycin administered in a pulse-dose regimen is as effective asother antibiotics tested in treating lesions of inflammatory acne.

Fernandez-Obregon compared daily systemic administration of doxycycline,erythromycin, minocycline, and tetracycline to three-times-weeklyadministration of azithromycin and found that the azithromycin treatmentregimen was as effective as the daily treatment regimens of the otherantibiotics in treating the lesions of inflammatory acne, even thoughazithromycin was administered at a much lower frequency than were theother antibiotics.

Treatment of acne with azithromycin, rather than with minocycline ordoxycycline, is desirable because of the broad range of deleterious sideeffects that are experienced by users of minocycline and doxycycline.Minocycline use has been associated with skin discoloration, centralnervous system effects such as dizziness and pseudomotor cerebri, and alupus-like syndrome. Doxycycline use has been associated withgastrointestinal upsets, erosive esophagitis and photosensitivity. Bothminocycline and doxycycline are also associated with candida vaginitis.Although there is some question as to whether azithromycin use may causecandida vaginitis, azithromycin has not been known to cause any of theother above side effects associated with minocycline or doxycycline.Additionally, minocycline and doxycycline are placed in PregnancyCategory D, which includes drugs that have some significant risks andthat should be used during pregnancy only when the alternatives areworse. In contrast, azithromycin is a Pregnancy Category B drug, whichcategory includes drugs that are used routinely and safely duringpregnancy and which are considered safe to use if there is a clinicalneed for the drug.

The Fernandez-Obregon study treated patients suffering from at least 12lesions of inflammatory acne, defined as papules, pustules, or cysts.Patients were graded on the reduction of the number of lesionsassociated with each treatment. The Fernandez-Obregon article did notdistinguish between the various types of inflammatory lesions and it ispossible, if not likely, that none of the patients treated had nodularor cystic lesions, or had at most one or two such lesions. Also, becausenodular or cystic acne is considered to be a distinct form of acnerequiring specific therapy and the intent of the Fernandez-Obregon studywas to compare the efficacy of azithromycin to that of otherantibiotics, which are known in the art to be efficacious to treatpapular and pustular inflammatory lesions but not nodular or cysticlesions, it is evident to one of skill of the art that the patientstreated in the Fernandez-Obregon study, although possibly having one ortwo cystic lesions, would not have been included in the study if theyhad been suffering from a distinct and more severe nodular acne. Asimilar study was reported by Singhi, M K, et al, “Comparison of OralAzithromycin Pulse with Daily Doxycycline in the Treatment of AcneVulgaris,” Indian Journal of Dermatology, Venereology, and Leprology,69(4):274-276 (2003). Singhi compared azithromycin given at a dose of500 mg for three consecutive days in a 10 day cycle with doxycyclinegiven daily to a population of individuals suffering from moderate tosevere inflammatory acne. Each of the individuals also received topicalerythromycin therapy throughout the study.

Each of the patients was graded for severity of acne prior tocommencement of therapy and at the end of therapy. The severity of acnewas graded counting the number of comedones, papules, pustules,infiltrated, and cystic lesions, multiplying the number of each type oflesion by the lesions severity index (0.5 for comedones, 1 for papule, 2for pustule, 3 for infiltrated lesion, and 4 for cyst), and summing theresults.

Like Fernandez-Obregon, Singhi does not disclose that any of thesubjects studied suffered from nodular acne and there is no suggestionthat any of the subjects had multiple acne nodules. The results ofSinghi were disclosed to be similar to those of Fernandez-Obregon andshowed that azithromycin is an effective medication for treatingmoderate to severe acne vulgaris.

It is clear from the disclosures of Fernandez-Obregon and Singhi thatnodular acne was not treated in their studies. Because an effectivetherapy for nodular acne that does not produce the severe side effectsof isotretinoin has long been sought, if either of these studies hadshown an effective antibiotic therapy against nodular or cystic acne,this result would have been proclaimed clearly as a breakthrough in acnetherapy.

Accordingly, the need persists to the present day for an effectivetherapy for nodular acne that does not present severe side effects, suchas those that occur with isotretinoin and possibly with tetracyclinefamily antibiotic therapy.

DESCRIPTION OF THE INVENTION

The inventors have unexpectedly discovered that systemic administrationof azithromycin is effective in treating nodules associated with acne,such as in patients suffering from nodular acne vulgaris. The inventorshave further discovered that systemic administration of azithromycin iseffective in treating the symptoms of severe nodular acne vulgaris.

As used herein, the term “acne” means acne vulgaris.

As used herein, the term “nodule” in the context of this applicationrefers to an acne lesion that is a palpable solid lesion greater than 5mm in diameter and which has depth within the skin.

As used herein, the term “acne (or inflammatory acne) with presence ofnodules” refers to acne vulgaris in which one or more acne nodules arepresent in the skin.

As used herein, the term “nodular acne” or “nodular acne vulgaris”refers to acne vulgaris in which three or more acne nodules are presentin the skin.

As used herein, the term “severe nodular acne” or “severe nodular acnevulgaris” refers to a case of acne vulgaris wherein an individualsuffering from the acne vulgaris has five or more acne nodules presentin the skin. Usually, patients with one or more acne nodules haveadditional manifestations of inflammatory acne, including multiplepapular or pustular lesions.

The invention is a method for treating acne nodules, such as due tonodular acne vulgaris. According to the method of the invention, apatient suffering from acne nodules, such as from nodular acne vulgaris,is systemically administered azithromycin in a dosage and for a timesufficient to reduce the number of acne nodules present in the skin ofthe patient. This results in an improvement in the appearance andself-image of the patient and reduces or eliminates the significant painand discomfort that are often associated with acne nodules. The patientmay be afflicted with acne with presence of nodules or from a moresevere form of acne, such as from nodular acne vulgaris or even fromsevere nodular acne vulgaris.

The azithromycin that is administered may be any pharmaceuticallyacceptable form of azithromycin that is effective in treating bacterialinfections or acne. Preferred forms of azithromycin include themonohydrate and dihydrate forms, such as disclosed in U.S. Pat. Nos.4,474,768; 4,517,359; and 6,268,489.

The patient of the method of the invention is typically a human but mayalso be a veterinary patient, such as a dog or cat. Human patients ofthe invention may be male or female and of any race and any age.Typically, the human patient of the invention is between 12 and 25 yearsold, although individuals younger than 12 years of age and older than 25years of age are also suitable for the method of the invention.

Administration of azithromycin in accordance with the invention is byany route by which azithromycin may be systemically administered.Examples of routes of administration in accordance with the inventioninclude parenteral routes, such as by intramuscular or subcutaneousinjection, and oral routes, such as by swallowing tablets, capsules,liquids, or powders containing azithromycin.

Many different regimens for administration of azithromycin to treat acnevulgaris and bacterial diseases have been utilized. It is conceived thatany of such regimens may be successfully utilized in connection with themethod of the present invention. The amount of azithromycin that isadministered in accordance with the invention is that which is effectiveto reduce the number of nodules in an individual afflicted with nodularor severe nodular acne vulgaris.

Thus, azithromycin may be administered in a pulsed dosing regimen. Forexample, azithromycin may be administered at a dosage of 250 mg ofazithromycin for 3 or 4 days, followed by a period of non-administrationof azithromycin for 3 to 7 days, and then repeated cycles of the 3 or 4day administration and 3 to 7 day non-administration. If desired, aloading dose of azithromycin, such as 500 mg, may be administered priorto the commencement of the daily 250 mg azithromycin. An alternativepulsed dosing regimen is by repeated cycles of one week of dailyadministration of 250 mg of azithromycin followed by one week of noadministration of azithromycin.

A preferred method of administration of azithromycin in accordance withthe method of the invention is daily dosing, that is non-pulsed dosing,of azithromycin. In this method of administration, a dosage ofazithromycin is administered daily until symptoms of nodular acne havelessened or have been eliminated.

Regardless of the dosing regimen that is utilized, administration ofazithromycin may be continued for a duration sufficient to reduce oreliminate signs and symptoms of nodular acne vulgaris. such as areduction in number of nodules. Preferably, there is a reduction of 66%or more in the number of nodules following treatment in accordance withthe invention compared to the number present at the initiation oftherapy. More preferably, the reduction is 75% or more. Most preferably,the reduction is 80% or more. In a most preferred embodiment, no nodulesremain following treatment. Although an improvement in nodular acne maybe obtained after only one or two weeks of treatment, a typical durationof therapy according to the invention is for a month or longer, andoften for 2, 3, or more months.

If desired, the azithromycin may be administered in combination withother topical or systemic, such as oral, medications or therapies thatare useful to treat the symptoms of acne. Skin cleansers andbactericidal agents such as benzoyl peroxide or azaleic acid andcomedolytic and keratolytic agents such as salicylic acid. alphahydroxyacids, and retinoids such as tretinoin, adapalene and tazarotene, areoften used in the treatment of acne. Topical antibiotics such aserythromycin, clindamycin, or tetracycline may be applied. It ispreferred that no systemic antibiotic, other than azithromycin, beadministered in accordance with the invention. Such combination systemicantibiotic therapy, even though not preferred, falls within the scope ofthe present invention. It is also within the scope of the invention touse azithromycin as described herein in conjunction with oralisotretinoin for the treatment of severe nodular acne. It is conceivedthat the administration of azithromycin may decrease the dose andduration of isotretinoin treatment needed, which is an importantconsideration considering the incidence and severity of side effects ofisotretinoin, or may increase the overall clinical effectiveness of theisotretinoin regimen.

The invention is further illustrated by the following non-limitingexamples. In the examples, patients included in the study were male orfemale subjects of any race, 16 years of age or older. presenting with20-60 inflammatory lesions (papules or pustules), 20 to 150non-inflammatory lesions (comedones or whiteheads), and 3 to 10 nodules.

EXAMPLE 1

Patients having severe acne vulgaris with multiple nodules were enrolledin an open label clinical study in which each patient received a dailyoral dose of 250 mg of azithromycin for the 3-month duration of thestudy. Lesion counts were recorded at baseline before the initiation oftreatment and at 1, 2, and 3 months following initiation of treatment.Of 18 patients that remained in the study longer than one month, only 2did not respond favorably to treatment. These 2 patients had 9 and 8nodules, respectively, at baseline and 8 and 13 nodules, respectivelytwo months after initiation of therapy. Of the favorable responders, twopatients who began the study with 3 nodules had 2 nodules at the end ofthe three month study. The remaining 14 patients who responded favorablyto treatment had on average 6.7 nodules at baseline (range 4 to 10nodules) and improved to having no nodules (10 patients) or at most 1nodule (4 patients) by the end of the three month course of treatment.

EXAMPLE 2

Another set of patients with severe acne vulgaris was enrolled in anopen label clinical study as in Example 1, except that each patientreceived a daily oral dose of 250 mg of azithromycin for one weekfollowed by one week of no azithromycin, which cycle was repeated forthe 3-month duration of the study. Of 18 patients that remained in thestudy longer than one month, only 2 did not respond favorably totreatment. These 2 patients had 6 and 10 nodules, respectively, atbaseline and 5 and 8 nodules, respectively, two months after initiationof therapy. Three patients had partial clearing of nodules during thestudy. These patients had 9, 10, and 6 nodules, respectively, atbaseline and 3, 4, and 2 nodules, respectively, at the end of the study.

The remaining 13 patients who responded favorably to treatment had onaverage 6.2 nodules at baseline (range 3 to 10 nodules) and improved tohaving no nodules (10 patients) or at most 1 nodule (3 patients) at theend of the three month course of treatment.

EXAMPLE 3

Another set of patients with severe acne vulgaris was enrolled in anopen label clinical study as in Example 1, except that each patientreceived a daily oral dose of 125 mg of azithromycin for the 3-monthduration of the study. Of 20 patients that remained in the study longerthan one month, only 2 did not respond favorably to treatment. These 2patients had 8 and 3 nodules, respectively, at baseline and 10 and 4nodules, respectively two months after initiation of therapy. The 18patients who responded favorably to treatment had on average 5.1 nodulesat baseline (range 3 to 8 nodules) and improved to having no nodules (13patients) or at most 1 nodule (5 patients) at the end of the three monthcourse of treatment.

Data from Examples 1 to 3 is summarized in Table 2.

TABLE 2 Example 2 250 mg/day Total Example 1 every Example 3 Examples250 mg/day other week 125 mg/day 1 to 3 Number of 18 18 20 56 patientsNumber of good 16 16 18 50 responders Percentage of 88.9 88.9 90.0 89.3good responders Number of 117 115 103 335 nodules Nodules 29 25 19 73remaining after treatment Percentage of 75.2 78.3 81.6 78.2 nodulescleared Number of 100 99 92 291 nodules in good responders Nodules ingood 8 12 5 25 responders after treatment Percentage of 92.0 87.9 94.691.4 nodules cleared in good responders

As shown in Examples 1 to 3 and in Table 2, systemic administration ofazithromycin is highly efficacious in treating nodular acne vulgaris,including severe nodular acne vulgaris The above data shows that about90% of individuals suffering from severe nodular acne who were treatedwith systemic azithromycin in accordance with the invention respondedfavorably to such treatment and that, in individuals respondingfavorably to this treatment, more than 90% of nodules were cleared.

The method of the invention provides a significant advance in thetreatment of nodules associated with acne as it provides a therapeuticoption for treating such difficult cases of acne that obviates the needto use isotretinoin, or reduces the amount or duration of isotretinointherapy that would otherwise be used. Additionally, treatment of acnenodules with azithromycin is more effective than treatment withtetracycline antibiotics such as minocycline or doxycycline. The methodof the invention, therefore, provides a valuable alternative in thetreatment of acne nodules, which is especially advantageous in view ofthe presence of side effects that occur with minocycline and doxycyclinetherapy.

Further modifications, uses, and applications of the invention describedherein will be apparent to those skilled in the art. It is intended thatsuch modifications be encompassed in the following claims.

1. A method for treating severe acne vulgaris present in the skin of anindividual suffering signs and symptoms therefrom comprisingsystemically administering azithromycin to the individual in an amountand for a time sufficient to ameliorate the signs and symptoms of thesevere acne vulgaris.
 2. The method of claim 1 wherein azithromycin isthe sole agent systemically administered to the individual for thetreatment of acne vulgaris.
 3. The method of claim 1 wherein thesystemic administration of the azithromycin is oral.
 4. The method ofclaim 3 wherein the azithromycin is in the form of a tablet.
 5. Themethod of claim 1 wherein the azithromycin is administered to theindividual in a dosage regimen lasting one month or longer.
 6. Themethod of claim 1 wherein the azithromycin is administered daily.
 7. Themethod of claim 1 wherein the azithromycin is administered in apulsed-dosing regimen.
 8. The method of claim 1 wherein the averagedosage of azithromycin administered over the course of treatment is 250mg/day or less.
 9. The method of claim 8 wherein, during each day of thecourse of treatment, the azithromycin is administered at a dosage of 250mg or less.
 10. The method of claim 9 wherein, during each day of thecourse of treatment, the azithromycin is administered at a dosage of 125mg or less.
 11. The method of claim 10 wherein the azithromycin isadministered to the individual in a dosage regimen lasting one month orlonger.
 12. The method of claim 1 wherein the azithromycin isadministered in conjunction with a systemic medication effective fortreating acne vulgaris.
 13. The method of claim 12 wherein the systemicmedication is isotretinoin.
 14. The method of claim 1 wherein theazithromycin is administered in combination with one or more topicalanti-acne therapies or medications.
 15. The method of claim 14 whereinthe topical anti-acne medication is a retinoid.
 16. The method of claim15 wherein the retinoid is selected from the group consisting oftretinoin, isotretinoin. adapalene and tazarotene.
 17. The method ofclaim 1 wherein a topical antibiotic is not co-administered with theazithromycin.
 18. The method of claim 1 wherein the form of azithromycinthat is administered is azithromycin monohydrate or azithromycindihydrate.
 19. The method of claim 1 wherein the severe acne vulgaris isat least as severe as defined as Grade 4 in the FDA IGA Scale for AcneVulgaris.
 20. A method for treating acne associated with nodules in anindividual suffering signs and symptoms therefrom comprisingsystemically administering azithromycin to the individual in an amountand for a time sufficient to ameliorate the signs and symptoms.
 21. Themethod of claim 20 wherein azithromycin is the sole agent systemicallyadministered to the individual for the treatment of acne vulgaris. 22.The method of claim 20 wherein the systemic administration of theazithromycin is oral.
 23. The method of claim 22 wherein theazithromycin is in the form of a tablet.
 24. The method of claim 20wherein the azithromycin is administered to the individual in a dosageregimen lasting one month or longer.
 25. The method of claim 20 whereinthe azithromycin is administered daily.
 26. The method of claim 20wherein the azithromycin is administered in a pulsed-dosing regimen. 27.The method of claim 20 wherein the average dosage of azithromycinadministered over the course of treatment is 250 mg/day or less.
 28. Themethod of claim 27 wherein, during each day of the course of treatment,the azithromycin is administered at a dosage of 250 mg or less.
 29. Themethod of claim 28 wherein, during each day of the course of treatment,the azithromycin is administered at a dosage of 125 mg or less.
 30. Themethod of claim 29 wherein the azithromycin is administered to theindividual in a dosage regimen lasting one month or longer.
 31. Themethod of claim 20 wherein the azithromycin is administered inconjunction with a systemic medication effective for treating acnevulgaris.
 32. The method of claim 31 wherein the systemic medication isisotretinoin.
 33. The method of claim 20 wherein the azithromycin isadministered in combination with one or more topical anti-acne therapiesor medications.
 34. The method of claim 33 wherein the topical anti-acnemedication is a retinoid.
 35. The method of claim 34 wherein theretinoid is selected from the group consisting of tretinoin,isotretinoin, adapalene and tazarotene.
 36. The method of claim 20wherein the form of azithromycin that is administered is azithromycinmonohydrate or azithromycin dihydrate.
 37. The method of claim 20wherein the acne is at least as severe as defined as Grade 4 in the FDAIGA Scale for Acne Vulgaris.